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EP2742040B1 - Composes d'indazole, compositions pharmaceutiques et procedes d'utilisation de ceux-ci - Google Patents

Composes d'indazole, compositions pharmaceutiques et procedes d'utilisation de ceux-ci Download PDF

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Publication number
EP2742040B1
EP2742040B1 EP12750354.8A EP12750354A EP2742040B1 EP 2742040 B1 EP2742040 B1 EP 2742040B1 EP 12750354 A EP12750354 A EP 12750354A EP 2742040 B1 EP2742040 B1 EP 2742040B1
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EP
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Prior art keywords
pyrazol
optionally substituted
indazole
halogen
carboxamide
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EP12750354.8A
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German (de)
English (en)
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EP2742040A1 (fr
Inventor
Jason Burch
Richard A. Goldsmith
Daniel Fred Ortwine
Richard Pastor
Zhonghua Pei
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

Definitions

  • Compounds of formula I which are inhibitors of ITK kinase, as well as compositions containing these compounds, and methods of use including, but not limited to, in vitro, in situ and in vivo diagnosis or treatment of mammalian cells.
  • ITK is a Tec family kinase that is expressed in T cells, NKT cells, NK cells, and mast cells. ITK is activated downstream of antigen engagement of the T cell receptor (TCR) and mediates TCR signals through the phosphorylation and activation of PLCg. Mice in which ITK is deleted showed defective differentiation of T cells towards to the Th2 subset, but not the Th1 subset. Additional studies indicate that Th2 cytokine production, but not early Th2 lineage commitment, is defective in ITK-deficient mouse T cells. Th2 cells promote allergic inflammation, and ITK knock-out mice have reduced lung inflammation, mucus production, and airway hyperreactivity in models of allergic asthma.
  • TCR T cell receptor
  • ITK kinase There exists a need for inhibitors of ITK kinase and treatments of diseases and disorders mediated by ITK kinase.
  • An aspect includes a compound of formula I: stereoisomers or a pharmaceutically acceptable salt thereof, wherein X, X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are described herein.
  • Another aspect includes a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I, stereoisomers or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier, diluent or excipient.
  • Another aspect includes a method of treating a disease responsive to the inhibition of ITK kinase in a patient, comprising administering an effective amount of a compound of formula I, stereoisomers or a pharmaceutically acceptable salt thereof
  • Another aspect includes a method of treating an immunological or inflammatory disease in a patient, comprising administering an effective amount of a compound of formula I, stereoisomers or a pharmaceutically acceptable salt thereof
  • Another aspect includes the use of a compound of formula I, stereoisomers or a pharmaceutically acceptable salt thereof in therapy.
  • Another aspect includes the use of a compound of formula I, stereoisomers or a pharmaceutically acceptable salt thereof in the treatment of a disease responsive to the inhibition of ITK kinase.
  • Another aspect includes the use of a compound of formula I, stereoisomers or a pharmaceutically acceptable salt thereof in the treatment of an immunological or inflammatory disease.
  • Another aspect includes the use of a compound of formula I, stereoisomers or a pharmaceutically acceptable salt thereof for the preparation of medicament for the treatment treatment of an immunological or inflammatory disease.
  • Another aspect includes a method of manufacturing a compound of formula I, comprising reacting a comopund of formula 1-3 or a salt thereof, with a comopund of formula 1-4 or a salt thereof, wherein PG is an amino protecting group and Lv is a leaving group, to form a compound of formula I.
  • Acyl means a carbonyl containing substituent represented by the formula -C(O)-R in which R is hydrogen, alkyl, a cycloalkyl, a heterocyclyl, cycloalkyl-substituted alkyl or heterocyclyl-substituted alkyl wherein the alkyl, alkoxy, cycloalkyl and heterocyclyl are as defined herein.
  • Acyl groups include alkanoyl (e.g. acetyl), aroyl (e.g. benzoyl), and heteroaroyl (e.g. pyridinoyl).
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical, wherein the alkyl radical may be optionally substituted independently with one or more substituents described herein.
  • the alkyl radical is one to eighteen carbon atoms (C 1 -C 18 ).
  • the alkyl radical is C 0 -C 6 , C 0 -C 5 , C 0 -C 3 , C 1 -C 12 , C 1 -C 10 , C 1 -C 8 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 or C 1 -C 3 .
  • C 0 alkyl refers to a bond.
  • alkyl groups include methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl,-C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ),
  • alkenyl refers to linear or branched-chain monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon double bond, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having "cis” and “trans” orientations, or alternatively, "E” and "Z” orientations.
  • the alkenyl radical is two to eighteen carbon atoms (C 2 -C 18 ).
  • the alkenyl radical is C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 -C 6 or C 2 -C 3 .
  • alkoxy refers to a linear or branched monovalent radical represented by the formula -OR in which R is alkyl, alkenyl, alkynyl or cycloalkyl, which can be further optionally substituted as defined herein.
  • Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, mono-, di- and tri-fluoromethoxy and cyclopropoxy.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon, triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein.
  • the alkynyl radical is two to eighteen carbon atoms (C 2 -C 18 ).
  • the alkynyl radical is C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 -C 6 or C 2 -C 3 .
  • Examples include, but are not limited to, ethynyl (-C ⁇ CH), prop-1-ynyl (-C ⁇ CCH 3 ), prop-2-ynyl (propargyl, -CH 2 C ⁇ CH), but-1-ynyl, but-2-ynyl and but-3-ynyl.
  • Alkylene refers to a saturated, branched or straight chain hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
  • the divalent alkylene group is one to eighteen carbon atoms (C 1 -C 18 ).
  • the divalent alkylene group is C 0 -C 6 , C 0 -C 5 , C 0 -C 3 , C 1 -C 12 , C 1 -C 10 , C 1 -C 8 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , or C 1 -C 3 .
  • the group C 0 alkylene refers to a bond.
  • Example alkylene groups include methylene (-CH 2 -), 1,1-ethyl (-CH(CH 3 )-), (1,2-ethyl (-CH 2 CH 2 -), 1,1-propyl (-CH(CH 2 CH 3 )-), 2,2-propyl (-C(CH 3 ) 2 -), 1,2-propyl (-CH(CH 3 )CH 2 -), 1,3-propyl (-CH 2 CH 2 CH 2 -), 1,1-dimethyleth-1,2-yl (-C(CH 3 ) 2 CH 2 -), 1,4-butyl (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • Alkenylene refers to an unsaturated, branched or straight chain hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.
  • the alkenylene group is two to eighteen carbon atoms (C 2 -C 18 ).
  • the alkenylene group is C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 -C 6 or C 2 -C 3 .
  • Alkynylene refers to an unsaturated, branched or straight chain hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.
  • the alkynylene radical is two to eighteen carbon atoms (C 2 -C 18 ).
  • the alkynylene radical is C 2 -C 12 , C 2 -C 10 , C 2 -C 8 , C 2 -C 6 or C 2 -C 3 .
  • Example alkynylene radicals include: acetylene (-C ⁇ C-), propargyl (-CH 2 C ⁇ C-), and 4-pentynyl (-CH 2 CH 2 CH 2 C ⁇ C-).
  • Amidine means the group -C(NH)-NHR in which R is hydrogen, alkyl, a cycloalkyl, a heterocyclyl, cycloalkyl-substituted alkyl or heterocyclyl-substituted alkyl wherein the alkyl, alkoxy, cycloalkyl and heterocyclyl are as defined herein.
  • a particular amidine is the group-NH-C(NH)-NH 2 .
  • Amino means primary (i.e., -NH 2 ), secondary (i.e., -NRH) and tertiary (i.e., -NRR) amines, that are optionally substituted, in which R is alkyl, alkoxy, a cycloalkyl, a heterocyclyl, cycloalkyl-substituted alkyl or heterocyclyl-substituted alkyl wherein the alkyl, alkoxy, cycloalkyl and heterocyclyl are as defined herein
  • Particular secondary and tertiary amines are alkylamine, dialkylamine, arylamine, diarylamine, aralkylamine and diaralkylamine wherein the alkyl is as herein defined and optionally substituted.
  • Particular secondary and tertiary amines are methylamine, ethylamine, propylamine, isopropylamine, phenylamine, benzylamine dimethylamine, diethylamine, dipropylamine and diisopropylamine.
  • amino-protecting group refers to a derivative of the groups commonly employed to block or protect an amino group while reactions are carried out on other functional groups on the compound.
  • protecting groups include carbamates, amides, alkyl and aryl groups, imines, as well as many N-heteroatom derivatives which can be removed to regenerate the desired amine group.
  • Particular amino protecting groups are Pmb (p-Methoxybenzyl), Boc (tert-Butyloxycarbonyl), Fmoc (9-Fluorenylmethyloxycarbonyl) and Cbz (Carbobenzyloxy). Further examples of these groups are found in T. W. Greene and P. G. M.
  • Aryl when used alone, or as part of another term, means a carbocyclic aromatic group, whether or not fused to one or more groups, having the number of carbon atoms designated, or if no number is designated, up to 14 carbon atoms.
  • One example includes aryl groups having 6-14 carbon atoms.
  • Another example inlcudes aryl groups having 6-10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, and the like (see e.g.
  • aryl is phenyl.
  • Substituted phenyl or substituted aryl means a phenyl group or aryl group substituted with one, two, three, four or five, for example 1-2, 1-3 or 1-4 substituents chosen from groups specified herein.
  • optional substituents on aryl are selected from halogen (F, Cl, Br, I), hydroxy, protected hydroxy, cyano, nitro, alkyl (for example C 1 -C 6 alkyl), alkoxy (for example C 1 -C 6 alkoxy), benzyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, arylsulfonylamino, arylsulfonylaminoalkyl, heterocyclylsulfonylamino, heterocyclylsulfonylaminoalkyl, heterocyclyl, aryl, or other groups specified.
  • halogen F, Cl, Br, I
  • alkyl for example C 1 -C 6 alkyl
  • substituted phenyl include a mono- or di(halo)phenyl group such as 2-chlorophenyl, 2-bromophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl and the like; a mono- or di(hydroxy)phenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 3- or
  • substituted phenyl represents disubstituted phenyl groups where the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl, and the like, as well as trisubstituted phenyl groups where the substituents are different, for example 3-methoxy-4-benzyloxy-6-methyl sulfonylamino, 3-methoxy-4-benzyloxy-6-phenyl sulfonylamino, and tetrasubstituted phenyl groups where the substituents are different such as 3-methoxy-4-benzyloxy-5-methyl-6-phenyl sulfonylamino.
  • Particular substituted phenyl groups include the 2-chlorophenyl, 2-aminophenyl, 2-bromophenyl, 3-methoxyphenyl, 3-ethoxy-phenyl, 4-benzyloxyphenyl, 4-methoxyphenyl, 3-ethoxy-4-benzyloxyphenyl, 3,4-diethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4-(1-chloromethyl)benzyloxy-6-methyl sulfonyl aminophenyl groups.
  • Fused aryl rings may also be substituted with any, for example 1, 2 or 3, of the substituents specified herein in the same manner as substituted alkyl groups.
  • cancer and “cancerous”, “neoplasm”, “tumor” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • a “tumor” comprises one or more cancerous cells. Examples of cancer include carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
  • cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small- cell lung cancer, non-small cell lung cancer ("NSCLC”), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, melanoma, multiple myeloma and B-cell lymphoma, brain, as well as head and neck cancer, and associated metastases.
  • NSCLC non-small cell lung cancer
  • chemotherapeutic agent is an agent useful in the treatment of a given disorder, for example, cancer or inflammatory disorders.
  • chemotherapeutic agents include NSAIDs; hormones such as glucocorticoids; corticosteroids such as hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, prednisone, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, halcinonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, aclometasone dipropionate, beta
  • calicheamicin especially calicheamicin gammall and calicheamicin omegaI1 (see, e.g., Nicolaou et al., Angew. Chem Intl. Ed. Engl., 33: 183-186 (1994 )); CDP323, an oral alpha-4 integrin inhibitor; dynemicin, including dynemicin A; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubic
  • celecoxib or etoricoxib include proteosome inhibitor (e.g. PS341); bortezomib (VELCADE®); CCI-779; tipifarnib (R11577); orafenib, ABT510; Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®); pixantrone; EGFR inhibitors (see definition below); farnesyltransferase inhibitors such as lonafarnib (SCH 6636, SARASAR TM ); and pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin (ELOXATIN TM ) combined with 5-FU and leucovorin.
  • Additional chemotherapeutic agents as defined herein include “anti-hormonal agents” or “endocrine therapeutics” which act to regulate, reduce, block, or inhibit the effects of hormones that can promote the growth of cancer. They may be hormones themselves, including, but not limited to: anti-estrogens with mixed agonist/antagonist profile, including, tamoxifen (NOLVADEX®), 4-hydroxytamoxifen, toremifene (FARESTON®), idoxifene, droloxifene, raloxifene (EVISTA®), trioxifene, keoxifene, and selective estrogen receptor modulators (SERMs) such as SERM3; pure anti-estrogens without agonist properties, such as fulvestrant (FASLODEX®), and EM800 (such agents may block estrogen receptor (ER) dimerization, inhibit DNA binding, increase ER turnover, and/or suppress ER levels); aromatase inhibitors, including steroidal aromatase inhibitors such as
  • Additional chemotherapeutic agents include therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).
  • therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituxim
  • Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizum
  • Chemotherapeutic agents also include "EGFR inhibitors,” which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an "EGFR antagonist.”
  • EGFR inhibitors refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity
  • Examples of such agents include antibodies and small molecules that bind to EGFR.
  • antibodies which bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, US Patent No.
  • EMD 55900 Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996 )
  • EMD7200 (matuzumab) a humanized EGFR antibody directed against EGFR that competes with both EGF and TGF-alpha for EGFR binding (EMD/Merck); human EGFR antibody, HuMax-EGFR (GenMab); fully human antibodies known as E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6. 3 and E7.6.
  • the anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immunoconjugate (see, e.g., EP659,439A2 , Merck Patent GmbH).
  • EGFR antagonists include small molecules such as compounds described in US Patent Nos: 5,616,582 , 5,457,105 , 5,475,001 , 5,654,307 , 5,679,683 , 6,084,095 , 6,265,410 , 6,455,534 , 6,521,620 , 6,596,726 , 6,713,484 , 5,770,599 , 6,140,332 , 5,866,572 , 6,399,602 , 6,344,459 , 6,602,863 , 6,391,874 , 6,344,455 , 5,760,041 , 6,002,008 , and 5,747,498 , as well as the following PCT publications: WO98/14451 , WO98/50038 , WO99/09016 , and WO99/24037 .
  • EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA ® Genentech/OSI Pharmaceuticals); PD 183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSAJ) 4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-pipe
  • Chemotherapeutic agents also include "tyrosine kinase inhibitors" including the EGFR-targeted drugs noted in the preceding paragraph; small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Rat-1 inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1 signaling; non-HER targeted TK
  • Chemotherapeutic agents also include asthma treatment agents, including inhaled corticosteroids such as fluticasone, budesonide, mometasone, flunisolide and beclomethasone; leukotriene modifiers, such as montelukast, zafirlukast and zileuton; long-acting beta agonists, such as salmeterol and formoterol; combinations of the above such as combinations of fluticasone and salmeterol, and combinations of budesonide and formoterol; theophylline; short-acting beta agonists, such as albuterol, levalbuterol and pirbuterol; ipratropium; oral and intravenous corticosteroids, such as prednisone and methylprednisolone; omalizumab; lebrikizumab; antihistamines; and decongestants; cromolyn; and ipratropium.
  • corticosteroids such as
  • NSAID non-steroidal anti-inflammatory drug
  • NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase.
  • NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib.
  • acetic acid derivatives such as indomethacin
  • sulindac sulindac
  • NSAIDs can be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.
  • conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to-moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.
  • chemotherapeutic agents include pharmaceutically acceptable salts, acids or derivatives of any of chemotherapeutic agents, described herein, as well as combinations of two or more of them.
  • Cycloalkyl refers to a non-aromatic, saturated or partially unsaturated hydrocarbon ring group wherein the cycloalkyl group may be optionally substituted independently with one or more substituents described herein.
  • the cycloalkyl group is 3 to 12 carbon atoms (C 3 -C 12 ).
  • cycloalkyl is C 3 -C 8 , C 3 -C 10 or C 5 -C 10 .
  • the cycloalkyl group, as a monocycle is C 3 -C 8 , C 3 -C 6 or C 5 -C 6 .
  • the cycloalkyl group, as a bicycle is C 7 -C 12 .
  • the cycloalkyl group is C 5 -C 12 .
  • monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, perdeuteriocyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
  • Exemplary arrangements of bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems.
  • Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane.
  • Examples of spiro cycloalkyl include, spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane.
  • Carboxy-protecting group refers to those groups that are stable to the conditions of subsequent reaction(s) at other positions of the molecule, which may be removed at the appropriate point without disrupting the remainder of the molecule, to give the unprotected carboxy-group.
  • carboxy protecting groups include, ester groups and heterocyclyl groups. Ester derivatives of the carboxylic acid group may be employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound.
  • ester groups include substituted arylalkyl, including substituted benzyls, such as 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, alkyl or substituted alkyl esters such as methyl, ethyl, t-butyl allyl or t-amyl, triphenylmethyl (trityl), 4-methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-phenylprop-2-yl, thioesters such as t-butyl thio
  • carboxy-protecting groups are heterocyclyl groups such as 1,3-oxazolinyl. Further examples of these groups are found in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 2nd ed., John Wiley & Sons, Inc., New York, N.Y., 1991, chapter 5 ; E. Haslam, "Protective Groups in Organic Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5 , and T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, NY, 1981, Chapter 5 .
  • the term "protected carboxy” refers to a carboxy group substituted with one of the above carboxy-protecting groups.
  • Guanidine means the group -NH-C(NH)-NHR in which R is hydrogen, alkyl, alkoxy, a cycloalkyl, a heterocyclyl, cycloalkyl -substituted alkyl or heterocyclyl-substituted alkyl wherein the alkyl, alkoxy, cycloalkyl and heterocyclyl are as defined herein.
  • a particular guanidine is the group -NH-C(NH)-NH 2 .
  • “Hydroxy-protecting group” refers to a derivative of the hydroxy group commonly employed to block or protect the hydroxy group while reactions are carried out on other functional groups on the compound.
  • protecting groups include tetrahydropyranyloxy, benzoyl, acetoxy, carbamoyloxy, benzyl, and silylethers (e.g. TBS, TBDPS) groups. Further examples of these groups are found in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 2nd ed., John Wiley & Sons, Inc., New York, NY, 1991, chapters 2-3 ; E. Haslam, "Protective Groups in Organic Chemistry", J.
  • protected hydroxy refers to a hydroxy group substituted with one of the above hydroxy-protecting groups.
  • Heterocyclic group “heterocyclic”, “heterocycle”, “heterocyclyl”, or “heterocyclo” alone, and when used as a moiety in a complex group such as a heterocycloalkyl group, are used interchangeably and refer to any mono-, bi-, tricyclic or spiro, saturated or unsaturated, aromatic (heteroaryl) or non-aromatic, ring system, having 3 to 20 ring atoms, where the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen.
  • heterocyclyl includes 3-12 ring atoms and includes monocycles, bicycles, tricycles and spiro ring systems, wherein the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen.
  • heterocyclyl includes 1 to 4 heteroatoms.
  • heterocyclyl includes 3- to 7-membered monocycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen.
  • heterocyclyl includes 4- to 6-membered monocycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen.
  • heterocyclyl includes 3-membered monocycles.
  • heterocyclyl includes 4-membered monocycles.
  • heterocyclyl includes 5-6-membered monocycles.
  • the heterocyclyl group includes 0 to 3 double bonds.
  • Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g. NO, SO, SO 2 ), and any nitrogen heteroatom may optionally be quaternized (e.g. [NR 4 ] + Cl - , [NR 4 ] + OH - ).
  • Example heterocycles are oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, aze
  • Examples of 5-membered heterocycles containing a sulfur or oxygen atom and one to three nitrogen atoms are thiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl.
  • Example 5-membered ring heterocycles containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as 1H-tetrazol-5-yl.
  • Example benzo-fused 5-membered heterocycles are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl.
  • Example 6-membered heterocycles contain one to three nitrogen atoms and optionally a sulfur or oxygen atom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl.
  • pyridyl such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl
  • pyrimidyl such as pyrimid-2-yl and pyrimid-4-yl
  • triazinyl such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl
  • pyridine N-oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the 1,3,4-triazin-2-yl groups are other example heterocycle groups.
  • Substituents for "optionally substituted heterocycles" include hydroxyl, alkyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, halo-substituted alkyl, amino, cyano, nitro, amidino, guanidino.
  • Heteroaryl alone and when used as a moiety in a complex group such as a heteroaralkyl group, refers to any mono-, bi-, or tricyclic ring system where at least one ring is a 5- or, 6-membered aromatic ring containing from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and in an example embodiment, at least one heteroatom is nitrogen. See, for example, Lang's Handbook of Chemistry, supra. Included in the definition are any bicyclic groups where any of the above heteroaryl rings are fused to an aryl ring.
  • heteroaryl includes 4-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen.
  • heteroaryl includes 5-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen.
  • Example heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, imidazol[1,2-a]pyrimidinyl and purinyl, as well as benzo-fused derivatives, for example benzoxazolyl, benzofuryl,
  • heteroaryl groups are: 1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl sodium salt, 1,2,4-thiadiazol-5-yl, 3-methyl-1,2,4-thiadiazol-5-yl, 1,3,4-triazol-5-yl, 2-methyl-1,3,4-triazol-5-yl, 2-hydroxy-1,3,4-triazol-5-yl, 2-carboxy-4-methyl-1,3,4-triazol-5-yl sodium salt, 2-carboxy-4-methyl-1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 2-methyl-1,3,4-oxadiazol-5-yl, 2-(hydroxymethyl)-1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,
  • a heterocyclyl group is attached at a carbon atom of the heterocyclyl group.
  • carbon bonded heterocyclyl groups include bonding arrangements at position 2, 3, 4, 5, or 6 of a pyridine ring, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine ring, position 2, 3, 5, or 6 of a pyrazine ring, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole ring, position 2, 4, or 5 of an oxazole, imidazole or thiazole ring, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of an aziridine ring, position 2, 3, or 4 of an azetidine ring, position 2, 3, 4, 5, 6, 7, or 8 of a quino
  • the heterocyclyl group is N-attached.
  • the nitrogen bonded heterocyclyl or heteroaryl group include bonding arrangements at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
  • leaving group refers to a portion of a first reactant in a chemical reaction that is displaced from the first reactant in the chemical reaction.
  • Examples of leaving groups include, but are not limited to, halogen atoms, alkoxy and sulfonyloxy groups.
  • Example sulfonyloxy groups include, but are not limited to, alkylsulfonyloxy groups (for example methyl sulfonyloxy (mesylate group) and trifluoromethylsulfonyloxy (triflate group)) and arylsulfonyloxy groups (for example p -toluenesulfonyloxy (tosylate group) and p -nitrosulfonyloxy (nosylate group)).
  • alkylsulfonyloxy groups for example methyl sulfonyloxy (mesylate group) and trifluoromethylsulfonyloxy (triflate group)
  • arylsulfonyloxy groups for example p -toluenesulfonyloxy (tosylate group) and p -nitrosulfonyloxy (nosylate group)
  • Optionally substituted unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g. 0, 1, 2, 3 or 4) of the substituents listed for that group in which said substituents may be the same or different. In an embodiment an optionally substituted group has 1 substituent. In another embodiment an optionally substituted group has 2 substituents. In another embodiment an optionally substituted group has 3 substituents.
  • divalent groups are described generically without specific bonding configurations, for example in the group -CH 2 C(O)-. It is understood that the generic description is meant to include both bonding configurations, unless specified otherwise.
  • R 1 -R 2 -R 3 if the group R 2 is described as -CH 2 C(O)-, then it is understood that this group can be bonded both as R 1 -CH 2 C(O)-R 3 , and as R 1 -C(O)CH 2 -R 3 , unless specified otherwise.
  • Package insert is used to refer to instructions customarily included in commercial packages of therapeutic products that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products.
  • “Pharmaceutically acceptable salts” include both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid
  • “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly base addition salts are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • Particularly organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.
  • a "sterile" formulation is aseptic or free from all living microorganisms and their spores.
  • Stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, conformers and the like.
  • Chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.
  • Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • racemic mixture and racemate refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • a “solvate” refers to an association or complex of one or more solvent molecules and a compound of the present invention.
  • solvents that form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • hydrate refers to the complex where the solvent molecule is water.
  • a "subject,” “individual,” or “patient” is a vertebrate.
  • the vertebrate is a mammal.
  • Mammals include, but are not limited to, farm animals (such as cows), sport animals, pets (such as cats, dogs, and horses), primates, mice and rats.
  • a mammal is a human.
  • “Therapeutically effective amount” means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein.
  • the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer.
  • the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic.
  • efficacy can, for example, be measured by assessing the time to disease progression (TTP) and/or determining the response rate (RR).
  • the therapeutic effective amount is an amount sufficient to decrease or alleviate an allergic disorder, the symptoms of an autoimmune and/or inflammatory disease, or the symptoms of an acute inflammatory reaction (e.g. asthma).
  • a therapeutically effective amount is an amount of a chemical entity described herein sufficient to significantly decrease the activity, expression or number of Th2 cytokines or B-cells.
  • Treatment refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, stabilized ( i.e ., not worsening) state of disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, prolonging survival as compared to expected survival if not receiving treatment and remission or improved prognosis.
  • compounds of the invention are used to delay development of a disease or disorder or to slow the progression of a disease or disorder.
  • Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder, (for example, through a genetic mutation) or those in which the condition or disorder is to be prevented.
  • compound(s) of this invention and “compound(s) of the present invention”, unless otherwise indicated, include compounds of formula I and stereoisomers, tautomers, solvates, metabolites, isotopes, salts (e.g., pharmaceutically acceptable salts), and prodrugs thereof.
  • One aspect includes a compound of formula I: stereoisomers or a pharmaceutically acceptable salt thereof, wherein:
  • Certain embodiments include a compound of formula I, stereoisomers or a pharmaceutically acceptable salt thereof, wherein:
  • compounds of formula I are other than:
  • X, X 1 , X 2 and X 3 are C.
  • R 1 and R 4 are independently hydrogen, halogen or -OR 7 .
  • X 3 is N; R 4 does not exist; and X, X 1 , and X 2 are C.
  • R 1 is does not exist, hydrogen, halogen or -OR 7 , wherein R 1 is optionally substituted by R 9 .
  • R 1 is hydrogen or -OCH 3 .
  • R 1 is hydrogen, F or -OCH 3 .
  • R 2 is does not exist, hydrogen, halogen, -OR 7 or 5-6-membered heterocyclyl wherein R 2 is optionally substituted by R 9 .
  • R 2 is hydrogen, F, -OCH 3 , pyrazolyl or pyridinyl.
  • R 2 is hydrogen, halogen, CF 3 , CN or -NR 7 R 8 .
  • R 2 is 3-10 membered heterocyclyl optionally substituted by R 9 .
  • R 2 is dihydro-2H-pyrano[2,3-b]pyridinyl, pyridzainyl, oxazolyl, thiazolyl, pyrazinyl, pyrrolidinyl, azetidinyl, piperazinyl, 3,6-dihydropyridinyl, pyrazolyl, piperidinyl, 2,3-dihydropyrido[3,2-b][1,4]oxazin or pyrimidinyl, wherein R 2 is optionally substituted by R 9 .
  • R 2 is hydrogen, halogen, -OR 7 , CF 3 , CN or -NR 7 R 8 , dihydro-2H-pyrano[2,3-b]pyridinyl, pyridzainyl, oxazolyl, thiazolyl, pyrazinyl, pyrrolidinyl, azetidinyl, piperazinyl, 3,6-dihydropyridinyl, pyrazolyl, piperidinyl, 2,3-dihydropyrido[3,2-b][1,4]oxazin or pyrimidinyl, wherein R 1 is optionally substituted by R 9 .
  • R 3 is does not exist, hydrogen, halogen, -OR 7 , -NR 7 R 8 , C 1 -C 12 alkyl, 3-10-membered heterocyclyl or 6-10 membered aryl, wherein R 3 is optionally substituted by R 9 .
  • R 3 is hydrogen, methyl, ethyl, Cl, F, -CH 3 , -OCH 3 , phenyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl or imidizolyl, wherein R 3 is optionally substituted by R 9 .
  • R 3 is hydrogen, halogen, C 1 -C 6 alkyl, cycloalkyl, or -NR 7 R 8 , wherein said alkyl is optionally substituted by halogen or -OR 10 .
  • R 3 is hydrogen, halogen, -OR 7 , -NR 7 R 8 , C 1 -C 12 alkyl, 3-10-membered heterocyclyl or 6-10 membered aryl, wherein R 3 is optionally substituted by R 9 .
  • R 4 is does not exist, hydrogen or -OR 7 , wherein R 4 is optionally substituted by R 9 . In certain embodiments, R 4 hydrogen or -OCH 3 .
  • X, X 1 , X 2 and X 3 are C; and R 1 and R 4 are hydrogen.
  • X, X 1 , X 2 and X 3 are C; and R 1 , R 2 , R 3 and R 4 are independently hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, halogen, -CN, -OR 7 , -SR 7 , -NR 7 R 8 ,-CF 3 , -OCF 3 , -NO 2 , -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -NR 7 C(O)R 8 , -S(O) 1-2 R 7 , -NR 7 S(O) 1-2 R 8 , -S(O) 1-2 NR 7 R 8 , C 3 -C 6 cycloalkyl, 3-10-membered heterocyclyl or 6-10 membered aryl, wherein R 1 , R 2 , R 3 and R 4 are independently
  • R 1 , R 2 , R 3 and R 4 are independently do not exist, hydrogen, C 1 -C 12 alkyl, halogen, -OR 7 , 5-6-membered heterocyclyl or phenyl, wherein R 1 , R 2 , R 3 and R 4 are independently optionally substituted by R 9 .
  • R 1 , R 2 , R 3 and R 4 are independently hydrogen, C 1 -C 12 alkyl, halogen, -OR 7 , 5-6-membered heterocyclyl or phenyl, wherein R 1 , R 2 , R 3 and R 4 are independently optionally substituted by R 9 .
  • R 1 , R 2 , R 3 and R 4 are independently do not exist, hydrogen, methyl, 2-hydroxyethyl, F, Cl, -OCH 3 , pyrazolyl, pyridinyl, pyrimidinyl or phenyl, wherein R 1 , R 2 , R 3 and R 4 are independently optionally substituted by R 9 .
  • R 1 , R 2 , R 3 and R 4 are independently hydrogen, methyl, 2-hydroxyethyl, F, Cl, -OCH 3 , pyrazolyl, pyridinyl, pyrimidinyl or phenyl, wherein R 1 , R 2 , R 3 and R 4 are independently optionally substituted by R 9 .
  • R 1 , R 3 and R 4 are independently do not exist, hydrogen, halogen or C 1 -C 12 alkyl
  • R 2 is hydrogen, C 1 -C 12 alkyl, halogen, -OR 7 , 5-6-membered heterocyclyl or phenyl, wherein R 1 , R 2 , R 3 and R 4 are independently optionally substituted by R 9 .
  • R 1 , R 3 and R 4 are independently hydrogen, halogen or C 1 -C 12 alkyl
  • R 2 is hydrogen, C 1 -C 12 alkyl, halogen, -OR 7 , 5-6-membered heterocyclyl or phenyl, wherein R 1 , R 2 , R 3 and R 4 are independently optionally substituted by R 9 .
  • R 1 , R 3 and R 4 are independently do not exist or hydrogen, and R 2 is does not exist, hydrogen, F, -OCH 3 or 5-6-membered heterocyclyl, wherein R 2 is optionally substituted by R 9 .
  • R 1 , R 3 and R 4 are hydrogen, and R 2 is hydrogen, F, -OCH 3 or 5-6-membered heterocyclyl, wherein R 2 is optionally substituted by R 9 .
  • R 1 , R 3 and R 4 are independently do not exist or hydrogen, and R 2 is pyrazolyl or pyridinyl optionally substituted by R 9 .
  • R 1 , R 2 and R 4 are independently do not exist, hydrogen, halogen or C 1 -C 12 alkyl
  • R 3 is hydrogen, C 1 -C 12 alkyl, halogen, -OR 7 , 5-6-membered heterocyclyl or phenyl, wherein R 1 , R 2 , R 3 and R 4 are independently optionally substituted by R 9 .
  • R 1 , R 2 and R 4 are independently do not exist or hydrogen and R 3 is hydrogen, C 1 -C 12 alkyl, halogen, -OR 7 , 5-6-membered heterocyclyl or phenyl, wherein R 3 is independently optionally substituted by R 9 .
  • R 1 , R 2 and R 4 are independently do not exist or hydrogen and R 3 is C 1 -C 12 alkyl, halogen, -OR 7 , 5-6-membered heterocyclyl or phenyl, wherein R 3 is independently optionally substituted by R 9 .
  • R 1 , R 2 and R 4 are independently do not exist or hydrogen and R 3 is 5-membered heterocyclyl optionally substituted by R 9 . In certain embodiments, R 1 , R 2 and R 4 are hydrogen and R 3 is 5-membered heterocyclyl optionally substituted by R 9 .
  • R 1 , R 2 and R 4 are independently do not exist or hydrogen and R 3 is pyrazolyl optionally substituted by R 9 . In certain embodiments, R 1 , R 2 and R 4 are hydrogen and R 3 is pyrazolyl optionally substituted by R 9 .
  • R 1 , R 2 and R 4 are independently do not exist or hydrogen and R 3 is 6-membered heterocyclyl optionally substituted by R 9 . In certain embodiments, R 1 , R 2 and R 4 are hydrogen and R 3 is 6-membered heterocyclyl optionally substituted by R 9 .
  • R 1 , R 2 and R 4 are independently do not exist or hydrogen and R 3 is pyridinyl or pyrimidinyl optionally substituted by R 9 . In certain embodiments, R 1 , R 2 and R 4 are hydrogen and R 3 is pyridinyl or pyrimidinyl optionally substituted by R 9 .
  • R 5 is C 1 -C 6 alkylene optionally substituted by halogen, oxo, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, -OR 16 , -SR 16 , -NR 16 R 17 , -CN, -CF 3 , -OCF 3 , - C(O)R 16 , -C(O)OR 16 , -NR 16 C(O)R 17 , -NR 16 S(O) 1-2 R 17 , 3-10-membered heterocyclyl or 6-10 membered aryl, and wherein said alkyl, alkenyl, alkynyl, heterocyclyl and phenyl are independently optionally substituted with R 9 .
  • R 5 is C 1 -C 6 alkylene optionally substituted by halogen, oxo, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, -OR 16 , -SR 16 , -NR 16 R 17 , -CN, -CF 3 , -OCF 3 , wherein said alkyl, alkenyl and alkynyl are independently optionally substituted with oxo or halogen;
  • R 5 does not exist
  • R 6 is hydrogen, C 3 -C 10 cycloalkyl, 3-10-membered heterocyclyl or 6-10-membered aryl, wherein R 6 is independently optionally substituted by R 9 .
  • R 5 does not exist and R 6 is hydrogen so that -R 5 -R 6 taken together is hydrogen.
  • R 5 is -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 (CH 3 )CH 2 -, - CH 2 CH(CH 3 ) 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH(CH 2 CH 3 )CH 2 CH 2 -, -CH(CH 3 )-, ( R )-CH(CH 3 )-, ( S )-CH(CH 3 )-, ( R )-CH(CH(CH 3 ) 2 )-, ( S )-CH(CH(CH 3 ) 2 )-, -CH(CH 2 CH 3 )-, -CH(CH 2 CH 3 )-, ( R )-CH(CH 2 CH 3 )-, ( S )-CH(CH 2 CH 3 )- or -C(CH 3 ) 2 -, wherein R 5 is independently optionally substituted by halogen, oxo, C 1
  • R 5 is C 1 -C 6 alkylene optionally substituted by -OH or -N(CH 3 ) 2 .
  • R 6 is hydrogen
  • R 6 is C 3 -C 10 cycloalkyl, wherein R 6 is independently optionally substituted by R 9 .
  • R 6 is cyclohexyl, cyclobutyl or norbornyl, wherein R 6 is independently optionally substituted by R 9 .
  • R 6 is 5-10-membered heterocyclyl or phenyl, wherein R 6 is independently optionally substituted by R 9 .
  • R 6 is imidazolyl, pyrrolidinyl, azetidinyl, pyridazinyl, chromanyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, morpholinyl, oxetanyl, phenyl, pyrazolyl, benzisoxazolyl, furanyl, isoxazolyl, benzothiazolyl, thiazolyl, thienyl, pyridinyl, piperidinyl, imidazo[1,2-a]pyridinyl or quinolinyl, wherein R 6 is independently optionally substituted by R 9 .
  • R 6 is hydrogen, cyclohexyl, cyclobutyl, norbornyl, imidazolyl, pyrrolidinyl, azetidinyl, pyridazinyl, chromanyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, morpholinyl, oxetanyl, phenyl, pyrazolyl, benzisoxazolyl, furanyl, isoxazolyl, benzothiazolyl, thiazolyl, thienyl, pyridinyl, piperidinyl, imidazo[1,2-a]pyridinyl or quinolinyl, wherein R 6 is independently optionally substituted by R 9 .
  • R 6 is phenyl, pyrazolyl, benzisoxazolyl, furanyl, isoxazolyl, benzothiazolyl, thiazolyl, thienyl, pyridinyl, piperidinyl, imidazo[1,2-a]pyridinyl or quinolinyl, wherein R 6 is independently optionally substituted by R 9 .
  • R 7 and R 8 are independently hydrogen or C 1 -C 6 alkyl, wherein said alkyl is independently optionally substituted by halogen, -CN, -CF 3 , -OCF 3 , oxo or C 1 -C 6 alkyl optionally substituted by halogen or oxo; or
  • R 7 and R 8 are independently taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6 alkyl optionally substituted by halogen or oxo.
  • each R 7 and R 8 are independently hydrogen or methyl.
  • R 8 is independently 3-6-membered heterocyclyl independently optionally substituted by halogen, -CN, -CF 3 , -OCF 3 , oxo or C 1 -C 6 alkyl optionally substituted by halogen or oxo.
  • R 8 is independently piperidinyl, pyrrolidinyl, tetrahydropyranyl, wherein R 8 is independently optionally substituted by halogen, -CN, -CF 3 , - OCF 3 , oxo or C 1 -C 6 alkyl optionally substituted by halogen or oxo.
  • each R 9 is independently hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkynyl, halogen, -CN, -(C 0 -C 6 alkylene)OR 10 , -(C 0 -C 6 alkylene)NR 10 R 11 , -CF 3 , -(C 0 -C 6 alkylene)C(O)OR 10 , -(C 0 -C 6 alkylene)C(O)NR 10 R 11 , -(C 0 -C 6 alkylene)(5-6-membered heterocyclyl), -(C 0 -C 6 alkylene)C(O)(5-6-membered heterocyclyl) or phenyl, wherein each R 9 is independently optionally substituted by halogen, oxo, -CF 3 , -CN, -OR 12 , -SR 12 , -NR 12 R 13 , -C(O)R 12 ,
  • each R 9 is independently hydrogen, methyl, ethyl, propyl, -CN, -OCH 3 , -OH, -C(O)OCH 3 , -C(O)OH, -C(O)NH 2 , -CF 3 , -OCF 3 , Br, Cl, F, -CH 3 , -C(CH 3 ) 2 OH, -NH 2 , -CH 2 N(CH 3 ) 2 , -NH(CH 3 ), -N(CH 3 )CH 2 OH, -CH 2 OH, morpholinyl, -C(O)piperidinyl, ethynyl, piperazinyl, pyridinyl, tetrazolyl, phenyl, -C(O)NH(CH 3 ), -CH 2 morpholinyl, isopropyl, thienyl,
  • each R 10 and R 11 is independently hydrogen or C 1 -C 6 alkyl optionally substituted by halogen or oxo, wherein said alkyl is independently optionally substituted by halogen or oxo; or
  • R 10 and R 11 are independently taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6 alkyl optionally substituted by halogen or oxo.
  • each R 10 and R 11 is independently hydrogen or C 1 -C 6 alkyl.
  • each R 12 and R 13 is independently hydrogen or methyl.
  • each R 14 and R 15 is independently hydrogen or methyl.
  • each R 16 and R 17 are independently hydrogen or C 1 -C 6 alkyl, wherein said alkyl is independently optionally substituted by halogen or oxo; or
  • R 16 and R 17 are independently taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6 alkyl optionally substituted by halogen or oxo.
  • each R 16 and R 17 are independently hydrogen or C 1 -C 6 alkyl.
  • each R 18 and R 19 is independently hydrogen or methyl.
  • each R 20 and R 21 are independently hydrogen or methyl.
  • X, X 1 , X 2 and X 3 are C, R 1 and R 4 are hydrogen, R 5 is C 1 -C 6 alkylene, wherein said alkylene, alkenylene and alkynylene are independently optionally substituted by halogen, oxo, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, -OR 16 , -SR 16 , - NR 16 R 17 , -CN, -C(O)R 16 , -C(O)OR 16 , -NR 16 C(O)R 17 , -NR 16 S(O) 1-2 R 17 , -CF 3 , -OCF 3 , 3-10-membered heterocyclyl or 6-10 membered aryl, and wherein said alkyl, alkenyl, alkynyl, heterocyclyl and phenyl are independently optionally substituted with R 9 ; and R
  • each R 12-21 is independently hydrogen or methyl.
  • Another aspect includes a compound selected from Examples 1-140, stereoisomers or a pharmaceutically acceptable salt thereof.
  • Another aspect includes a compound selected from Examples 1-279, stereoisomers or a pharmaceutically acceptable salt thereof.
  • tautomeric forms of compounds of formula I Another aspect includes tautomeric forms of compounds of formula I.
  • the term "tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • a prodrug of formula I is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a salt of such compound.
  • Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of a compound of the present invention.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, cirtulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.
  • prodrugs are also encompassed.
  • a free carboxyl group of a compound of Formula I can be derivatized as an amide or alkyl ester.
  • compounds of this invention comprising free hydroxy groups may be derivatized as prodrugs by converting the hydroxy group into a group such as, but not limited to, a phosphate ester, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl group, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115 .
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • More specific examples include replacement of the hydrogen atom of the alcohol group with a group such as (C 1 -C 6 )alkanoyloxymethyl, 1-((C 1 -C 6 )alkanoyloxy)ethyl, 1-methyl-1-((C 1 -C 6 )alkanoyloxy)ethyl, (C 1 -C 6 )alkoxycarbonyloxymethyl, N-(C 1 -C 6 )alkoxy-carbonylaminomethyl, succinoyl, (C 1 -C 6 )alkanoyl, ⁇ -amino(C 1 -C 4 )alkanoyl, arylacyl and ⁇ -aminoacyl, or ⁇ -aminoacyl- ⁇ -aminoacyl, where each ⁇ -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 , -P(O)(O(C 1 -C 6 )alky
  • Another aspect includes isotopically-labeled compounds of formula I, which are structurally identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses.
  • Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I and 125 I.
  • Certain isotopically-labeled compounds of the present invention e.g., those labeled with 3 H and 14 C
  • Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are useful for their ease of preparation and detectability.
  • isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • salts of compounds of the present invention include those salts prepared by reaction of a compound of formula I with a mineral or organic acid or an inorganic base, such salts including, but not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyn-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,
  • the compounds of the present invention may include mono, di or tri-salts in a single compound.
  • the salt is a pharmaceutically acceptable acid addition salt.
  • the salt is a pharmaceutically acceptable base addition salt.
  • the compounds of formula I also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of formula I and/or for separating enantiomers of compounds of formula I.
  • a “metabolite” is a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, glucuronidation, and the like, of the administered compound.
  • another aspect includes metabolites of compounds of formula I, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
  • Metabolites are identified, for example, by preparing a radiolabelled (e.g., 14 C or 3 H) isotope of a compound of the invention, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to a human, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite).
  • a detectable dose e.g., greater than about 0.5 mg/kg
  • the metabolite structures are determined in conventional fashion, e.g., by MS, LC/MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well known to those skilled in the art. The metabolites, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention.
  • Compounds of this invention may be synthesized by synthetic routes that include processes analogous to those well known in the chemical arts, particularly in light of the description contained herein.
  • the starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, WI) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, N.Y. (1967-1999 ed .), or Beilsteins Handbuch der organischen Chemise, 4, Aufl. ed. Springer-Verlag, Berl in, including supplements).
  • Compounds of formula I may be prepared singly or as compound libraries comprising 2 or more compounds, for example 5 to 1,000 compounds, or 10 to 100 compounds.
  • Libraries of compounds of formula I may be prepared by a combinatorial 'split and mix' approach or by multiple parallel syntheses using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.
  • a compound library comprising at least 2 compounds of formula I.
  • Schemes 1-2 show a general method for preparing the compounds of the present invention as well as key intermediates.
  • Examples section below For a more detailed description of the individual reaction steps, see the Examples section below.
  • Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds described herein.
  • specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions.
  • many of the compounds prepared by the methods described below can be further modified in light of this disclosure using chemistry known to those skilled in the art.
  • Scheme 1 shows a method of preparing compounds of formula I, wherein R 1 -R 6 are defined herein for formula I.
  • Pyrazoles 1-1 can be alkylated to give alkylated pyrazoles 1-2, using alkylating agents such as alkylhalides or substituted alkylhalides (for example ethylbromide, bromomethylbenzene or 1-bromomethyl-3-chlorobenzene), or using Mitsunobu type alkylating conditions using triphenylphosphine, a diamide, such as DEAD, and a hydroxyalkyl or substituted hydroxyalkyl group (for example 1-phenylethanol or 3-(dimethylamino)-1-phenylpropan-1-ol).
  • alkylating agents such as alkylhalides or substituted alkylhalides (for example ethylbromide, bromomethylbenzene or 1-bromomethyl-3-chlorobenzene)
  • Alkylated pyrazoles 1-2 can be reduced to give the amino pyrazoles 1-3 using conditions such as transition metal catalyzed hydrogenation or reductions, such as palladium and hydrogen gas or tin halide salts in acidic solutions.
  • Amino pyrazoles 1-3 can be coupled with imidazo carboxcylic acids 1-4 to form amides 1-5 using amide coupling conditions.
  • Amides 1-5 can be further derivatized by coupling reactions when one or more of R 1 , R 2 , R 3 and R 4 are independently halogen (as exemplified in Scheme 2), to form derivatized amides 1-6.
  • Scheme 2 shows an example method of cross coupling amides 2-1 to form derivatized compounds 2-2 or 2-3.
  • Halogenated-amide 2-1 is cross-coupled using a transition metal catalyst, for example palladium, with an aryl- or heterocyclyl-substituted substrate (wherein M is for example a boronic acid or ester, or a zinc, copper, tin or magnesium organometallic).
  • a transition metal catalyst for example palladium
  • M is for example a boronic acid or ester, or a zinc, copper, tin or magnesium organometallic.
  • Scheme 3 shows a method of preparing compounds of formula I, wherein R 1 -R 6 are defined herein for formula I.
  • Acids 1-4 can be coupled with amino pyrazoles to form amides 3-1.
  • Amides 3-1 can be alkylated to form alkylated amides 1-5. Alkylated amides can then be deprotected to form compounds of formula I.
  • amides 3-1 can be derivatized when one or more of R 1 -R 4 are indepenedently halogen to form derivatized amides 3-4, which can be alkylated to form compounds 3-5 and deprotected to form compounds 3-3.
  • compounds 3-5 contain halogen in R 6 , then further coupling reactions can lead to derivatized compounds 3-6, which can be deprotected to form compounds 3-3.
  • Scheme 4 shows a method of preparing compounds of formula I, wherein R 1 -R 6 are defined herein for formula I.
  • acids 4-1, 4-2, 4-3 or 4-4 can be coupled with compound 1-3 to form the amides 4-5, 4-6, 4-7 or 4-8.
  • the amides can be further derivatized according to similar reactions as shown in Scheme 1, to form compounds of formula I.
  • the compound 1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid can be made according to Lynch et al. Can. J. Chem.
  • compounds of formula I may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • physiologically acceptable carriers i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8.
  • a compound of formula I is formulated in an acetate buffer, at pH 5.
  • the compounds of formula I are sterile.
  • the compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aque
  • compositions are formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the "effective amount" of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit ITK kinase activity in a cell. For example, such amount may be below the amount that is toxic to normal cells, or the mammal as a whole.
  • the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01-100 mg/kg, alternatively about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
  • oral unit dosage forms such as tablets and capsules, preferably contain from about 25-100 mg of the compound of the invention.
  • the compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • the compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • buffers stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing
  • An example of a suitable oral dosage form is a tablet containing about 25mg, 50mg, 100mg, 250mg, or 500mg of the compound of the invention compounded with about 30-90 mg anhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30 mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mg magnesium stearate.
  • the powdered ingredients are first mixed together and then mixed with a solution of the PVP.
  • the resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment.
  • An example of an aerosol formulation can be prepared by dissolving the compound, for example 5-400 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired.
  • the solution may be filtered, e.g., using a 0.2 micron filter, to remove im
  • One aspect therefore, includes a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
  • Another embodiment includes a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I and a therapeutically inert carrier, diluent or excipient.
  • Another embodiment includes a pharmaceutical composition comprising a compound of Formula I for use in the treatment of a disease responsive to the inhibition of ITK kinase. Another embodiment includes a pharmaceutical composition comprising a compound of Formula I for use in the treatment of a immunological or inflammatory disease. Another embodiment includes a pharmaceutical composition comprising a compound of Formula I for use in the treatment of asthma or atopic dermatitis.
  • ITK is activated downstream of antigen engagement of the T cell receptor (TCR) and mediates TCR signals through the phosphorylation and activation of PLCg.
  • Mice in which ITK is deleted showed defective differentiation of T cells towards to the Th2 subset, but not the Th1 subset. Additional studies indicate that Th2 cytokine production, but not early Th2 lineage commitment, is defective in ITK-deficient mouse T cells. Th2 cells promote allergic inflammation, and ITK knock-out mice have reduced lung inflammation, mucus production, and airway hyperreactivity in models of allergic asthma.
  • the compounds of the invention inhibit the activity of ITK kinase. Accordingly, the compounds of the invention are useful for the treatment of inflammation and immunological diseases.
  • Inflammatory diseases which can be treated according to the methods of this invention include, but are not limited to, asthma, allergic rhinitis, atopic dermatitis, rheumatoid arthritis, psoriasis, contact dermatitis, and delayed hypersensitivity reactions.
  • An embodiment includes a method of treating or preventing a disease responsive to the inhibition of ITK kinase in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of Formula I, a stereoisomer or pharmaceutically acceptable salt thereof.
  • An embodiment includes use of a compound of Formula I, a stereoisomer or pharmaceutically acceptable salt thereof in therapy.
  • Another embodiment includes use of a compound of Formula I, a stereoisomer or pharmaceutically acceptable salt thereof in treating or preventing a disease responsive to the inhibition of ITK kinase.
  • Another embodiment includes use of a compound of Formula I, a stereoisomer or pharmaceutically acceptable salt thereof in treating or preventing an inflammatory disease.
  • Another embodiment includes use of a compound of Formula I, a stereoisomer or pharmaceutically acceptable salt thereof in treating asthma, allergic rhinitis, atopic dermatitis, rheumatoid arthritis, psoriasis, contact dermatitis, and delayed hypersensitivity reactions.
  • Another embodiment includes use of a compound of Formula I, a stereoisomer or pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an inflammatory disease.
  • Another embodiment includes use of a compound of Formula I, a stereoisomer or pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of asthma, allergic rhinitis, atopic dermatitis, rheumatoid arthritis, psoriasis, contact dermatitis, and delayed hypersensitivity reactions.
  • Another embodiment includes the use of a compound of Formula I, a stereoisomer or pharmaceutically acceptable salt thereof for the preparation of a medicament for treating or preventing an inflammatory disease.
  • Another embodiment includes the use of a compound of Formula I, a stereoisomer or pharmaceutically acceptable salt thereof for the preparation of a medicament for treating asthma, allergic rhinitis, atopic dermatitis, rheumatoid arthritis, psoriasis, contact dermatitis, and delayed hypersensitivity reactions.
  • Another embodiment includes a compound of Formula I, a stereoisomer or pharmaceutically acceptable salt thereof for treating or preventing an inflammatory disease.
  • Another embodiment includes a compound of Formula I, a stereoisomer or pharmaceutically acceptable salt thereof for treating asthma, allergic rhinitis, atopic dermatitis, rheumatoid arthritis, psoriasis, contact dermatitis, and delayed hypersensitivity reactions.
  • Another embodiment includes a compound of Formula I, a stereoisomer or pharmaceutically acceptable salt thereof for use in treating or preventing an inflammatory disease.
  • Another embodiment includes a compound of Formula I, a stereoisomer or pharmaceutically acceptable salt thereof for use in treating asthma, allergic rhinitis, atopic dermatitis, rheumatoid arthritis, psoriasis, contact dermatitis, and delayed hypersensitivity reactions.
  • Another embodiment includes the use of a compound of Formula I in therapy.
  • Another embodiment includes the use of a compound of Formula I in the treatment of an immunological or inflammatory disease.
  • Another embodiment includes the use of a compound of Formula I for the preparation of medicament for the treatment treatment of an immunological or inflammatory disease.
  • Another embodiment includes a compound of Formula I for use in the treatment of an immunological or inflammatory disease
  • Another embodiment includes a method of treating a disease responsive to the inhibition of ITK kinase in a patient, comprising administering an effective amount of a compound of Formula I, stereoisomers or a pharmaceutically acceptable salt thereof
  • Compounds of the invention are also useful for reducing inflammation in cells that overexpress ITK.
  • compounds of the invention are useful for reducing inflammation in cells that have aberrant or overactive antigen engagement of the T cell receptor.
  • compounds of the invention are useful for reducing inflammation in cells that have over-activation or phosphorylation of PLCg.
  • the compounds can be used for the treatment of inflammation or immunological disorders in cells that overexpress Th2 cytokine.
  • Another embodiment includes a method of treating or preventing cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of Formula I, a stereoisomer or pharmaceutically acceptable salt thereof.
  • the compounds of formula I may be employed alone or in combination with other chemotherapeutic agents for treatment.
  • the compounds of the present invention can be used in combination with one or more additional drugs, for example an anti-hyperproliferative, anticancer, cytostatic, cytotoxic, anti-inflammatory or chemotherapeutic agent.
  • the second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound of this invention such that they do not adversely affect each other.
  • agents are suitably present in combination in amounts that are effective for the purpose intended.
  • the compounds may be administered together in a unitary pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially. Such sequential administration may be close or remote in time.
  • compounds of the present invention are coadministered with a cytostatic compound selected from the group consisting of cisplatin, doxorubicin, taxol, taxotere and mitomycin C.
  • the cytostatic compound is doxorubicin.
  • compounds of the present invention are coadministered with an anti-inflammatory agent selected from a NSAID and corticosteroid.
  • compounds of the present invention are coadministered with any of anti-asthmtic agents, including but not limited to beta2-adrenergic agonists, inhaled and oral corticosteroids, leukotriene receptor antagonist, and omalizumab.
  • compounds of the present invention are coadministered with an anti-asthmtic agent selected from a NSAID, combinations of fluticasone and salmeterol, combinations of budesonide and formoterol, omalizumab, lebrikizumab and corticosteroid selected from fluticasone, budesonide, mometasone, flunisolide and beclomethasone.
  • an anti-rheumatoid agent in one example, RITUXAN®.
  • compounds of the present invention are coadministered with a chemotherapeutic agent selected from etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi), Interleukin 1 (IL-1) blockers such as anakinra (Kineret), monoclonal antibodies against B cells such as rituximab (RITUXAN®), T cell costimulation blockers such as abatacept (Orencia), Interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®); Interleukin 13 (IL-13) blockers such as lebrikizumab; Interferon alpha (IFN) blockers such as Rontalizumab; Beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as Anti-M1 prime; Secreted homotrimeric IL-1
  • the compounds of the present invention can be also used in combination with radiation therapy.
  • radiation therapy refers to the use of electromagnetic or particulate radiation in the treatment of neoplasia. Radiation therapy delivers doses of radiation sufficiently high to a target area to cause death of reproducing cells, in both tumor and normal tissues.
  • the radiation dosage regimen is generally defined in terms of radiation absorbed dose (rad), time and fractionation, and must be carefully defined by the oncologist. The amount of radiation a patient receives will depend on various considerations but two of the most important considerations are the location of the tumor in relation to other critical structures or organs of the body, and the extent to which the tumor has spread.
  • radiotherapeutic agents are provided in Hellman, Principles of Radiation Therapy, Cancer, in Principles I and Practice of Oncology, 24875 (Devita et al., 4th ed., vol 1, 1993 ).
  • Alternative forms of radiation therapy include three-dimensional conformal external beam radiation, intensity modulated radiation therapy (IMRT), stereotactic radiosurgery and brachytherapy (interstitial radiation therapy), the latter placing the source of radiation directly into the tumor as implanted "seeds".
  • IMRT intensity modulated radiation therapy
  • stereotactic radiosurgery stereotactic radiosurgery
  • brachytherapy interstitial radiation therapy
  • Another embodiment includes a method of manufacturing a compound of formula I, comprising reacting a comopund of formula 1-3 or a salt thereof, with a comopund of formula 1-4 or a salt thereof, wherein PG is an amino protecting group and Lv is a leaving group, to form a compound of formula I.
  • PG is a BOC group.
  • Lv is OH.
  • kits for treating a disease or disorder responsive to the inhibition of ITK kinase includes:
  • the kit further includes:
  • the instructions describe the simultaneous, sequential or separate administration of said first and second pharmaceutical compositions to a patient in need thereof.
  • the first and second compositions are contained in separate containers.
  • the first and second compositions are contained in the same container.
  • Containers for use include, for example, bottles, vials, syringes, blister pack, etc.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the container includes a compound of formula I or formulation thereof which is effective for treating the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • the container includes a composition comprising at least one compound of formula I.
  • the label or package insert indicates that the composition is used for treating the condition of choice, such as cancer.
  • the label or package inserts indicates that the composition comprising the compound of formula I can be used to treat a disorder.
  • the label or package insert may indicate that the patient to be treated is one having a disorder characterized by overactive or irregular kinase activity.
  • the label or package insert may also indicate that the composition can be used to treat other disorders.
  • the article of manufacture may comprise (a) a first container with a compound of formula I contained therein; and (b) a second container with a second pharmaceutical formulation contained therein, wherein the second pharmaceutical formulation comprises a chemotherapeutic agent.
  • the article of manufacture in this embodiment of the invention may further comprise a package insert indicating that the first and second compounds can be used to treat patients at risk of stroke, thrombus or thrombosis disorder.
  • the article of manufacture may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
  • BWFI bacteriostatic water for injection
  • phosphate-buffered saline such as bacteriostatic water for injection (BWFI),
  • This material was diluted in tetrahydrofuran (50 mL), cooled to 0 °C, then sodium hydride (0.417 g, 10.4 mmol) was added. The mixture was stirred at 0 °C for 30 minutes, then [ ⁇ -(trimethylsilyl)ethoxy]methyl chloride (1.85 mL, 10.4 mmol) was added dropwise. The mixture was allowed to slowly warm to room temperature over 90 minutes, then MeOH was added to quench excess hydride, and the mixture was concentrated in vacuo. The residue was diluted with 200 mL EtOAc, then washed with 200 mL brine.
  • the reaction vial was sealed and the reaction mixture was purged with a stream of N 2 via needle inlet/outlet for several minutes. The mixture was heated at 60°C for 3 hours. The reaction mixture was diluted with EtOAc and washed with water, saline and concentrated to dryness. The crude material was purified by CombiFlash (dry load) on a 12 G silica column, eluting with 10 - 90% EtOAc / heptanes to give 0.288 mg ethyl 6-(pyrrolidin-1-yl)-1H-indazole-3-carboxylate. To a solution of this material in Tetrahydrofuran (8 mL) was added Lithium hydroxide (0.133 g, 5.55 mmol).
  • reaction mixture was heated at 60 °C overnight.
  • This white powder was collected by vac. Filtration and taken into EtOAc and concentrated to give 250 mg (95%, 2 steps) of the title compound as a crystalline white powder.
  • the mixture was diluted with 5 mL CH 2 Cl 2 and 5 mL brine, filtered through a phase separator to remove the aqueous layer and concentrated in vacuo.
  • the residue was diluted with 1.0 mL trifluoroacetic acid, then triisopropylsilane (80.9 ⁇ L, 0.394 mmol) and a few drops of CH 2 Cl 2 were added.
  • the mixture was stirred for 2 hours at rt.
  • the mixture was concentrated in vacuo, then purified by automated reverse-phase HPLC, which provided 11 mg (32%) of the title compound.
  • Example 12 6-(1H-Pyrazol-4-yl)-1H-indazole-3-carboxylic acid [1-(4-carbamoyl-benzyl)-1H - pyrazol - 4 - yl]-amide
  • Example 13 6-(1H-Pyrazol-4-yl)-1H-indazole-3-carboxylic acid ⁇ 1-[2-(3,5-dimethyl-1H-pyrazol-4-yl)-ethyl]-1H-pyrazol-4-yl ⁇ -amide
  • Example 22 6-(1H-Pyrazol-4-yl)-1H-indazole-3-carboxylic acid ⁇ 1-[3-(4-hydroxy-piperidine-1-carbonyl)-benzyl]-1H-pyrazol-4-yl ⁇ -amide
  • the mixture was heated to 120 °C for 30 minutes in the microwave, then cooled to rt.
  • the mixture was diluted with 5 mL CH 2 Cl 2 and 5 mL brine, then filtered through a phase separator and concentrated in vacuo.
  • the residue was diluted with trifluoroacetic acid (1 mL), and triisopropylsilane (45.5 ⁇ L, 0.222 mmol) and a few drops of CH 2 Cl 2 to homogenize were added.
  • the mixture was stirred for 90 minutes at rt, then concentrated in vacuo. Purification by automated reverse phase HPLC provided 9.7 mg of the title compound.
  • the mixture was heated to 110 °C for 20 minutes in the microwave, then cooled to rt.
  • the mixture was diluted with 5 mL CH 2 Cl 2 and 5 mL brine and filtered through a phase separator. After in vacuo concentration, the residue was diluted with TFA (1 mL), triisopropylsilane (93 ⁇ L, 0.45 mmol) and a few drops of CH 2 Cl 2 to homogenize, and the mixture was stirred at 90 minutes at rt. After in vacuo concentration, the residue was purified by automated reverse phase HPLC to provide the title compound (12 mg; 0.0297 mmol; 33%).
  • Example 47 6-(1H-Pyrazol-4-yl)-1H-indazole-3-carboxylic acid ⁇ 1-[3-(1-hydroxy-1-methyl-ethyl)-benzyl]-1H-pyrazol-4-yl ⁇ -amide
  • Example 48 6-(1H-Pyrazol-4-yl)-1H-indazole-3-carboxylic acid ⁇ 1-[3-(2H-tetrazol-5-yl)-benzyl]-1H-pyrazol-4-yl ⁇ -amide
  • the title compound was synthesized according to Example 74, substituting 3-((4-amino-1 H- pyrazol-1-yl)methyl)benzonitrile for 1-(3-(4-amino-1 H -pyrazol-1-yl) propyl)piperidin-3-ol and 5-phenyl-1 H -indazole-3-carboxylic acid for 1 H -indazole-3-carboxylic acid.
  • Example 80 N -(1-(3-Cyanobenzyl)-1 H -pyrazol-4-yl)-5-(1 H -pyrazol-3-yl)-1 H -indazole-3-carboxamide
  • Example 80 The title compound was synthesized according to Example 80, substituting 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -pyrazole for 1-(tetrahydro-2 H -pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1 H -pyrazole.
  • the title compound was synthesized according to Example 89, substituting azetidine for dimethylamine HCl and N-(1-(4-formylbenzyl)-1H-pyrazol-4-yl)-1-trityl-1H-indazole-3-carboxamide for N-(1-(3-formylbenzyl)-1H-pyrazol-4-yl)-1-trityl-1H-indazole-3-carboxamide.
  • Example 104 N-(1-(4-((2-(dimethylamino)ethylamino)methyl)benzyl)-1H-pyrazol-4-yl)-1H-indazole-3-carboxamide
  • the aqueous phase was further extracted with 100 mL EtOAc, then the combined organic extracts were dried (Na 2 SO 4 ) and concentrated in vacuo.
  • the residue was diluted with 5 mL TFA, and triisopropylsilane (5 mmol) and a few drops of CH 2 Cl 2 were added. After stirring for 90 minutes at rt, the mixture was concentrated in vacuo, and the residue purified by automated reverse phase HPLC to provide the title compound.
  • ITK Invitrogen PV3875
  • LCMS liquid chromatography-mass spectrometry
  • ITK is incubated at room temperature with test compounds for 45 minutes in 100 mM 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (HEPES) buffer (pH 7.2) containing 10 mM MgCl 2 , 2 mM dithiothreitol (DTT), 20 ⁇ M adenosine-5'-triphosphate (ATP), 0.015% Brij 35, 2% dimethylsulfoxide (DMSO), and 2 ⁇ M (5-carboxyfluorescein)-EFPIYDFLPAKKK-NH 2 peptide substrate.
  • HEPES 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid
  • Examples 1-140 were tested in the above assay and the results of the tests are shown below in Table 2 (were + is 0.01-1 nM, ++ is 1-100 nM, and +++ is 100-3,500 nM or higher).
  • Table 2 Example# ITK Ki 1 ++ 2 ++ 3 ++ 4 +++ 5 +++ 6 ++ 7 ++ 8 ++ 9 ++ 10 ++ 11 ++ 12 + 13 ++ 14 ++ 15 ++ 16 ++ 17 ++ 18 ++ 19 ++ 20 ++ 21 ++ 22 ++ 23 ++ 24 + 25 ++ 26 ++ 27 + 28 ++ 29 + 30 + 31 ++ 32 ++ 33 ++ 34 ++ 35 ++ 36 + 37 + 38 ++ 39 + 40 + 41 ++ 42 ++ 43 ++ 44 ++ 45 ++ 46 + 47 ++ 48 + 49 ++ 50 ++ 51 ++ 52 ++ 53 ++ 54 ++ 55 ++ 56 ++ 57 ++ 58 ++ 59 ++ 60 +++ 61 +++ 62 ++ 63 ++ 64 +++ 65

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Claims (14)

  1. Composé de formule (I) :
    Figure imgb0344
     ses stéréoisomères ou un de leurs sels pharmaceutiquement acceptables, formule dans laquelle :
    X, X1 et X2 représentent C et X3 représente C ou N ;
    R1, R2, R3 ou R4, indépendamment, n'existent pas ou représentent un atome d'hydrogène, un groupe alkyle en C1 à C12, alcényle en C2 à C12, alcynyle en C2 à C12, halogéno, -CN, -OR7, -SR7, NR7R8, -CF3, -OCF3, -NO2, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -NR7C(O)R8, -S(O)1-2R7, -NR7S(O)1-2R8, -S(O)1-2NR7R8, cycloalkyle en C3 à C6, hétérocyclyle tri- à décagonal ou aryle hexa- à décagonal, les groupes R1, R2, R3 et R4 étant facultativement substitués indépendamment avec R9 ;
    R5 n'existe pas ou représente un groupe alkylène en C1 à C6, alcénylène en C2 à C6, alcynylène en C2 à C6, lesdits groupes alkylène, alcénylène et alcynylène étant facultativement substitués indépendamment avec des substituants halogéno, oxo, alkyle en C1 à C12, alcényle en C2 à C12, alcynyle en C2 à C12, -OR16, -SR16, -NR16R17, -CN, -C(O)R16, -C(O)OR16, -NR16C(O)R17, -NR16S(O)1-2R17, -CF3, -OCF3, hétérocyclyle tri- à décagonal ou aryle hexa- à décagonal, lesdits groupes alkyle, alcényle, alcynyle, hétérocyclyle et phényle étant facultativement substitués indépendamment avec R9 ;
    R6 représente un atome d'hydrogène, un groupe cycloalkyle en C3 à C10, hétérocyclyle tri- à décagonal ou aryle hexa- à décagonal, R6 étant facultativement substitué indépendamment avec R9 ;
    chacun de R7 et R8 représente indépendamment un atome d'hydrogène, un groupe alkyle en C1 à C6, cycloalkyle en C3 à C6, hétérocyclyle tri- à hexagonal ou phényle, lesdits groupes alkyle, cycloalkyle, hétérocyclyle et phényle étant facultativement substitués indépendamment avec des substituants halogéno, -CN, -CF3, -OCF3, oxo ou alkyle en C1 à C6 facultativement substitué avec un substituant halogéno ou oxo ; ou bien
    R7 et R8 sont pris indépendamment conjointement avec l'atome auquel ils sont fixés pour former un groupe hétérocyclyle tri- à hexagonal facultativement substitué avec un substituant halogéno, oxo ou alkyle en C1 à C6 facultativement substitué avec un substituant halogéno ou oxo ;
    chaque groupe R9 représente indépendamment un atome d'hydrogène, un groupe oxo, alkyle en C1 à C12, alcényle en C2 à C12, alcynyle en C2 à C12, halogéno, - (alkylène en C0 à C6)CN, -(alkylène en C0 à C6)OR10, -(alkylène en C0 à C6) SR10, -(alkylène en C0 à C6)NR10R11, -(alkylène en C0 à C6CF3, - (alkylène en C0 à C6) NO2, -(alkylène en C0 à C6) C(O)R10, - (alkylène en C0 à C6)C(O)OR10, -(alkylène en C0 à C6) C(O)NR10R11, (alkylène en C0 à C6) NR10C (O)R11, - (alkylène en C0 à C6) S(O)1-2R10, -(alkylene en C0 à C6) NR10S (O)1-2R11, - (alkylène en C0 à C6) S(O)1-2NR10R11, -(alkylène en C0 à C6) (cycloalkyle en C3 à C6), -(alkylène en C0 à C6) (hétérocyclyle tri- à décagonal), -(alkylène en C0 à C6)C(O) (hétérocyclyle tri- à décagonal) ou -(alkylène en C0 à C6)(aryle en C6 à C10), chaque groupe R9 étant facultativement substitué indépendamment avec un substituant halogéno, oxo, -CF3, -CN, -OR12, -SR12, -NR12R13, -C(O)R12, -S(O)1-2R12, alkyle en C1 à C6 facultativement substitué avec un substituant oxo ou halogéno, alcényle en C2 à C6 facultativement substitué avec un substituant oxo ou halogéno, ou alcynyle en C2 à C6 facultativement substitué avec un substituant oxo ou halogéno ;
    chacun de R10 et R11 représente indépendamment un atome d'hydrogène, un groupe alkyle en C1 à C6, alcényle en C2 à C6, alcynyle en C2 à C6, hétérocyclyle tri- à hexagonal, phényle ou cycloalkyle en C3 à C6, lesdits groupes alkyle, alcényle, alcynyle, hétérocyclyle, phényle et cycloalkyle étant facultativement substitués indépendamment avec des substituants oxo, -CF3, -OCF3, -OR14, -SR14, -NR14R15, -CN, hétérocyclyle tri- à hexagonal, phényle, cycloalkyle en C3 à C6 ou alkyle en C1 à C6 facultativement substitué avec un substituant halogéno ou oxo ; ou bien
    R10 et R11 sont pris indépendamment conjointement avec l'atome de carbone auquel ils sont fixés pour former un groupe hétérocyclyle tri- à hexagonal facultativement substitué avec un substituant halogéno, oxo ou alkyle en C1 à C6 facultativement substitué avec un substituant halogéno ou oxo ;
    chacun de R12 et R13 représente indépendamment un atome d'hydrogène ou un groupe alkyle en C1 à C6 facultativement substitué avec un substituant halogéno ou oxo ; ou bien
    R12 et R13 sont pris indépendamment conjointement avec l'atome auquel ils sont fixés pour former un groupe hétérocyclyle tri- à hexagonal facultativement substitué avec un substituant halogéno, oxo, ou alkyle en C1 à C6 facultativement substitué avec un substituant halogéno ;
    chacun de R14 et R15 représente indépendamment un atome d'hydrogène ou un groupe alkyle en C1 à C6 facultativement substitué avec un substituant halogéno ou oxo ; ou bien
    R14 et R15 sont pris indépendamment conjointement avec l'atome auquel ils sont fixés pour former un groupe hétérocyclyle tri- à hexagonal facultativement substitué avec un substituant halogéno, oxo, ou alkyle en C1 à C6 facultativement substitué avec un substituant halogéno ;
    chacun de R16 et R17 représente indépendamment un atome d'hydrogène, un groupe alkyle en C1 à C6, alcényle en C2 à C6, alcynyle en C2 à C6, hétérocyclyle tri- à hexagonal, phényle ou cycloalkyle en C3 à C6, lesdits groupes alkyle, alcényle, alcynyle, hétérocyclyle, phényle et cycloalkyle étant facultativement substitués indépendamment avec des substituants halogéno, oxo, -CF3, -OCF3, -OR18, -SR18, -NR18R19, -CN, hétérocyclyle tri- à hexagonal, phényle, cycloalkyle en C3 à C6 ou alkyle en C1 à C6 facultativement substitué avec un substituant halogéno, -OR20, -NR20R21, ou oxo ; ou bien
    R16 et R17 sont pris indépendamment conjointement avec l'atome auquel ils sont fixés pour former un groupe hétérocyclyle tri- à hexagonal facultativement substitué avec un substituant halogéno, oxo, ou alkyle en C1 à C6 facultativement substitué avec un substituant halogéno ou oxo ;
    chacun de R18 et R19 représente indépendamment un atome d'hydrogène ou un groupe alkyle en C1 à C6 facultativement substitué avec un substituant halogéno ou oxo ; ou bien
    R18 et R19 sont pris indépendamment conjointement avec l'atome auquel ils sont fixés pour former un groupe hétérocyclyle tri- à hexagonal facultativement substitué avec un substituant halogéno, oxo ou alkyle en C1 à C6 facultativement substitué avec un substituant halogéno ; et
    chacun de R20 et R21 représente indépendamment un atome d'hydrogène ou un groupe alkyle en C1 à C6 facultativement substitué avec un substituant halogéno ou oxo ; autre que
    N-(1-éthyl-1H-pyrazole-4-yl)-1H-indazole-3-carboxamide;
    5-amino-N-(1-éthyl-1H-pyrazole-4-yl)-1H-indazole-3-carboxamide ;
    5-amino-N-(1-méthyl-1H-pyrazole-4-yl)-1H-indazole-3-carboxamide ;
    N-[1-(imidazo[1,2-a]pyridine-2-ylméthyl)-1H-pyrazole-4-yl]-1H-indazole-3-carboxamide ;
    N-[1-[2-(diéthylamino)éthyl]-1H-pyrazole-4-yl]-1H-indazole-3-carboxamide ;
    N-(1-méthyl-1H-pyrazole-4-yl)-5-nitro-1H-indazole-3-carboxamide ;
    N-[1-[2-(3,4-diméthoxyphényl)éthyl]-1H-pyrazole-4-yl]-1H-indazole-3-carboxamide;
    acide 4-[(2H-indazole-3-ylcarbonyl)amino]-1H-pyrazole-1-acétique ;
    N-[1-[2-(phénylméthoxy)éthyl]-1H-pyrazole-4-yl]-1H-indazole-3-carboxamide ;
    N-[1-(4-cyanobutyl)-1H-pyrazole-4-yl]-1H-indazole-3-carboxamide ; ou
    N-[1-[(3-cyanophényl)méthyl]-1H-pyrazole-4-yl]-1H-indazole-3-carboxamide.
  2. Composé suivant la revendication 1, dans lequel X, X1, X2 et X3 représentent C.
  3. Composé suivant les revendications 1 et 2, dans lequel R1 et R4 représentent indépendamment un atome d'hydrogène, un groupe halogéno ou -OR7.
  4. Composé suivant les revendications 1 à 3, dans lequel R2 représente un atome d'hydrogène, un groupe halogéno, -OR7, CF3, CN ou -NR7R8, dihydro-2H-pyrano[2,3-b]-pyridinyle, pyridazinyle, oxazolyle, thiazolyle, pyrazinyle, pyrrolidinyle, azétidinyle, pipérazinyle, 3,6-dihydro-pyridinyle, pyrazolyle, pipéridinyle, 2,3-dihydro-pyrido[3,2-b][1,4]oxazine ou pyrimidinyle, R2 étant facultativement substitué avec R9.
  5. Composé suivant les revendications 1 à 4, dans lequel R3 représente un atome d'hydrogène, un groupe halogéno, -OR7, -NR7R8, alkyle en C1 à C12, hétérocyclyle tri- à décagonal ou aryle hexa- à décagonal, R3 étant facultativement substitué avec R9.
  6. Composé suivant les revendication 1 à 5, dans lequel R5 représente un groupe -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2(CH3)CH2-, -CH2CH(CH3)2-, -CH2CH2CH2CH2-, -CH2CH(CH2CH3)CH2CH2-, -CH(CH3)-, (R)-CH(CH3) -, (S)-CH(CH3) -, (R)-CH(CH(CH3)2) -, (S)-CH(CH(CH3)2) -, -CH(CH2CH3)-, -CH(CH2CH3)-, (R)-CH(CH2CH3)-, (S)-CH(CH2CH3) - ou -C(CH3)2-, R5 étant facultativement substitué indépendamment avec un substituant halogéno, oxo, alkyle en C1 à C12, alcényle en C2 à C12, alcynyle en C2 à C12, -OR16, -SR16, -NR16R17, -CN, -CF3, -OCF3, -C(O)R16, -C(O)OR16, -NR16C(O)R17, NR16S(O)1-2R17, hétérocyclyle tri- à décagonalou aryle hexa- à décagonal, lesdits groupes alkyle, alcényle, alcynyle, hétérocyclyle et phényle étant facultativement substitués indépendamment avec R9.
  7. Composé suivant les revendications 1 à 6, dans lequel R6 représente un atome d'hydrogène, un groupe cyclohexyle, cyclobutyle, norbornyle, imidazolyle, pyrrolidinyle, azétidinyle, pyridazinyle, chromanyle, pyrimidinyle, tétrahydrofuranyle, tétrahydropyranyle, dioxanyle, morpholinyle, oxétanyle, phényle, pyrazolyle, benzisoxazolyle, furanyle, isoxazolyle, benzothiazolyle, thiazolyle, thiényle, pyridinyle, pipéridinyle, imidazo[1,2-a]pyridinyle ou quinolinyle, R6 étant facultativement substitué indépendamment avec R9.
  8. Composé suivant les revendications 1 à 7, dans lequel R7 et R8 représentent indépendamment un atome d'hydrogène ou un groupe alkyle en C1 à C6, ledit groupe alkyle étant facultativement substitué indépendamment avec un substituant halogéno, -CN, -CF3, -OCF3, oxo ou alkyle en C1 à C6 facultativement substitué avec un substituant halogéno ou oxo ; ou bien R7 et R8 sont pris indépendamment conjointement avec l'atome auquel ils sont fixés pour former un groupe hétérocyclyle tri- à hexagonal facultativement substitué avec un substituant halogéno, oxo, ou alkyle en C1 à C6 facultativement substitué avec un substituant halogéno ou oxo.
  9. Composé suivant les revendications 1 à 8, dans lequel R9 représente indépendamment un atome d'hydrogène, un groupe méthyle, éthyle, propyle, -CN, -OCH3, -OH, -C(O)OCH3, -C(O)OH, -C(O)NH2, -CF3, -OCF3, Br, Cl, F, -CH3, -C(CH3)2OH, -NH2, -CH2N(CH3)2, -NH(CH3), -N(CH3)CH2OH, -CH2OH, morpholinyle, -C(O)pipéridinyle, éthynyle, pipérazinyle, pyridinyle, tétrazolyle, phényle, -C(O)NH(CH3), -CH2-morpholinyle, isopropyle, thiényle,
    Figure imgb0345
    Figure imgb0346
    Figure imgb0347
    Figure imgb0348
  10. Composé suivant les revendications 1 à 9, dans lequel chacun de R10 et R11 représente indépendamment un atome d'hydrogène ou un groupe alkyle en C1 à C6 facultativement substitué avec un substituant halogéno ou oxo, ledit groupe alkyle étant facultativement substitué indépendamment avec un substituant halogéno ou oxo ; ou bien R10 ou R11 sont pris indépendamment conjointement avec l'atome auquel ils sont fixés pour former un groupe hétérocyclyle tri- à hexagonal facultativement substitué avec un substituant halogéno, oxo, ou alkyle en C1 à C6 facultativement substitué avec un substituant halogéno ou oxo.
  11. Composé suivant les revendications 1 à 10, dans lequel chacun des groupes R12 à R21 représente indépendamment un atome d'hydrogène ou un groupe méthyle.
  12. Composition pharmaceutique comprenant un composé des revendications 1 à 11 et un support, diluant ou excipient thérapeutiquement inerte.
  13. Composé suivant les revendications 1 à 11, pour une utilisation dans le traitement d'une maladie immunologique ou inflammatoire.
  14. Procédé de production d'un composé des revendications 1 à 11, comprenant la réaction d'un composé de formule 1-3 :
    Figure imgb0349
     ou d'un de ses sels, avec un composé de formule 1-4 :
    Figure imgb0350
     ou un de ses sels, où PG représente un groupe protecteur de la fonction amino et Lv représente un groupe partant.
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